Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer

Abstract

Pancreatic cancer is projected to become the second deadliest cancer by 2030 in the United States, and the overall five-year survival rate stands still at around 9%. The stroma compartment can make up more than 90% of the pancreatic tumor mass, contributing to the hypoxic tumor microenvironment. The dense stroma with extracellular matrix proteins can be a physical and metabolic barrier reducing therapeutic efficacy. Cancer-associated fibroblasts are a source of extracellular matrix proteins. Therefore, targeting these cells, or extracellular matrix proteins, have been considered as therapeutic strategies. However, several studies show that deletion of cancer-associated fibroblasts may have tumor-promoting effects. Cancer-associated fibroblasts are derived from a variety of different cell types, such as pancreatic stellate cells and mesenchymal stem cells, and constitute a diverse cell population consisting of several functionally heterogeneous subtypes. Several subtypes of cancer-associated fibroblasts exhibit a tumor-restraining function. This review article summarizes recent findings regarding origin and functional heterogeneity of tumor-promoting as well as tumor-restraining cancer-associated fibroblasts. A better understanding of cancer-associated fibroblast heterogeneity could provide more specific and personalized therapies for pancreatic cancer patients in the future.

Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer

“…Mesenchymal stem cells (MSCs) exist in many tissues that have an important role in tissue regeneration [ 58 ]. However, MSCs (such as bone marrow-derived and adipose-derived MSCs) can migrate to tumors and differentiate into cancer-associated MSCs and tumor-promoting CAFs [ 10 , 58 ]. The complex cellular and molecular interaction, paracrine and reciprocal factors between MSCs and the surrounding microenvironment can lead to different function of MSCs and outcomes [ 10 , 58 ].…”

“…However, MSCs (such as bone marrow-derived and adipose-derived MSCs) can migrate to tumors and differentiate into cancer-associated MSCs and tumor-promoting CAFs [ 10 , 58 ]. The complex cellular and molecular interaction, paracrine and reciprocal factors between MSCs and the surrounding microenvironment can lead to different function of MSCs and outcomes [ 10 , 58 ]. However, MSCs can be used for anti-cancer treatment because of their characteristic tendency to home to tumor sites.…”

“…Rather than complete depletion of CAF subtypes, reprogramming active fibroblasts into quiescent fibroblasts or the tumor-promoting subtype of CAFs into the tumor-restraining subtype of CAFs can be deemed to block pancreatic cancer progression and to render cancer cells more responsive to treatment ( Figure 1 ) [ 10 , 19 ]. Vitamin D is a pluripotent fat-soluble prohormone and plays a critical role in calcium homeostasis, cell differentiation, proliferation as well as apoptosis.…”

“…It has been demonstrated that static normal fibroblasts suppress polyoma virus-transformed tumor cells [ 17 ], suggesting that an innate function of fibroblasts is to protect against tumorigenesis [ 18 ]. Several subtypes of cancer-associated fibroblasts exhibit a tumor-restraining function [ 10 , 19 ]. Therefore, identification and better characterization of tumor-promoting CAF subtypes is important.…”

“…Pancreatic cancer exhibits a significant Cancers 2021, 13, 697 2 of 14 resistance to established therapeutic options such as chemotherapy and radiotherapy, in part due to the dense stromal tumor microenvironment [8]. Cancer-associated fibroblasts (CAF) are the major stromal cell type and source of extracellular matrix proteins shaping a physical and metabolic barrier thereby reducing therapeutic efficacy [9,10]. Targeting CAFs and disrupting ECM have been considered as promising therapeutic strategies.…”